It is well established that environmental factors, such as early life adversity and adult chronic stress, have long-lasting effects on behavior and contribute to the development of psychiatric diseases. Although environmentally-induced epigenetic changes in DNA methylation and chromatin structure at some candidate disease genes have been implicated in the development of disease phenotypes, it is still unknown whether the epigenetic alterations are global or local and if they are a cause or a consequence of the phenotype. Our recent work with genome-wide epigenetic profiling of homogenous populations of hippocampal neurons showed that a wide range of environmental insults alter the epigenome at discrete domains. These epigenomic hotspots are characterized by specific features that distinguish them from the rest of the genome. The epigenomic hotspots are typically intragenic, located preferentially in exons, and found in introns of genes involved in synaptic plasticity and gene regulatory processes. We hypothesize that the presence of these epigenomic domains is evolutionarily beneficial because it allows rapid methylation changes at neuroplasticity genes in response to environmental inputs, which ultimately leads to adaptive changes in gene expression and behavior. However, sustained adverse environmental inputs can lock these environmentally-sensitive epigenomic domains into an irreversible state, resulting in loss of plasticity and maladaptive behavior. The discovery of these unique epigenomic domains has both basic and translation implications because they can mechanistically link environmental factors to the resultant behavioral phenotypes. Furthermore, they may be used as biomarkers, to assess prior stress exposure, and as pharmacological targets, to prevent and reverse adversity/stress induced psychopathology. To address these possibilities we propose to investigate the regulatory (Aim 1), neurobiological (Aim 2), and the potential diagnostic/clinical importance (Aim 3) of the identified epigenomic domains.